Abstract
BackgroundAutism is a neurodevelopmental disorder of unknown etiopathogenesis associated with structural and functional abnormalities of neurons and increased formation of reactive oxygen species. Our previous study revealed enhanced accumulation of amino-terminally truncated amyloid-β (Aβ) in brain neurons and glia in children and adults with autism. Verification of the hypothesis that intraneuronal Aβ may cause oxidative stress was the aim of this study.ResultsThe relationships between neuronal Aβ and oxidative stress markers—4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA)—were examined in the frontal cortex from individuals aged 7–32 years with idiopathic autism or with chromosome 15q11.2-q13 duplications (dup(15)) with autism, and age-matched controls. Quantification of confocal microscopy images revealed significantly higher levels of neuronal N-truncated Aβ and HNE and MDA in idiopathic autism and dup(15)/autism than in controls. Lipid peroxidation products were detected in all mitochondria and lipofuscin deposits, in numerous autophagic vacuoles and lysosomes, and in less than 5% of synapses. Neuronal Aβ was co-localized with HNE and MDA, and increased Aβ levels correlated with higher levels of HNE and MDA.ConclusionsThe results suggest a self-enhancing pathological process in autism that is initiated by intraneuronal deposition of N-truncated Aβ in childhood. The cascade of events includes altered APP metabolism and abnormal intracellular accumulation of N-terminally truncated Aβ which is a source of reactive oxygen species, which in turn increase the formation of lipid peroxidation products. The latter enhance Aβ deposition and sustain the cascade of changes contributing to metabolic and functional impairments of neurons in autism of an unknown etiology and caused by chromosome 15q11.2-q13 duplication.
Highlights
Autism is a neurodevelopmental disorder of unknown etiopathogenesis associated with structural and functional abnormalities of neurons and increased formation of reactive oxygen species
The percentage of amyloid-positive neurons as well as intraneuronal Aβ load were significantly higher in individuals diagnosed with idiopathic autism and in subjects diagnosed with dup (15) and autism spectrum disorder (ASD) than in controls [7]
The intraneuronal Aβ deposits immunoreacted with two antibodies against distinct Aβ epitopes: mAb 4G8, specific for the 17-21 aminoacids of the Aβ sequence (Figure 1a) and R226, specific for aa 36-42 of Aβ but revealed almost no reaction with mAb 6E10, specific for aa 4-13 of Aβ (Figure 1a), indicating that the deposits contained Nterminally truncated Aβ, consistent with Aβ 17-40/42 or Aβ 11-40/42, or other Aβ species
Summary
Autism is a neurodevelopmental disorder of unknown etiopathogenesis associated with structural and functional abnormalities of neurons and increased formation of reactive oxygen species. Our previous study revealed enhanced accumulation of amino-terminally truncated amyloid-β (Aβ) in brain neurons and glia in children and adults with autism. Our recent postmortem studies demonstrated intracellular deposits of Aβ truncated on the amino-terminal side—the Aβ17-40/42—in neurons and glia in the brain cortex, cerebellum and in subcortical nuclei. The percentage of amyloid-positive neurons as well as intraneuronal Aβ load were significantly higher in individuals diagnosed with idiopathic autism and in subjects diagnosed with dup (15) and autism spectrum disorder (ASD) than in controls [7]. Accumulation of full-length Aβ 1-42 and Aβ 1-40 in Alzheimer’s disease and Down syndrome is associated with production of reactive oxygen species and contributes to oxidative stress [8,9,10]
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